PHARMOCO-KINETICS AND DYNAMICS FOR OUTPATIENT ANAESTHESIA.

Johan C. Ræder, Dept. of Anaesth. Ullevaal Univ. Hospital, N-0407 Oslo

Outpatient anaesthesia is characterised by a high turn-over of elective, usually fairly healthy patients due for procedures of minor or intermediate invasiveness and duration. It is highly important to have a rapid and uneventful recovery, still being able to provide strong anaesthetic effect when needed during the procedure. Three consepts are important in this regard, all aiming at reducing the unwanted residual effects of in-appropriately given anaesthetic drugs:

- The drugs must be chosen after a careful evaluation of what are important effect and side-effect issues in the individual patient.

- The anaesthetic drugs should be easily titrate-able, both for onset and off-set.

- Optimal timing of drugs and drug combinations may reduce the total dose.

Pre-operative issues:

In the pre-operative phase a strategy should be outlined for the whole peri-operative period. Some patients may need preoperative anxiolyses, which should be accomplished without prolonging the recovery, i.e. a small dose of midazolam (2-3 mg IV) or a low rate infusion of propofol (1-2 mg/kg/h, target 0.5-1.0 mg/ml) may be instituted. However, most outpatients do not need any pre-operative medication for pain or anxiety, but preparations for proper postoperative analgesia may start in this phase. Paracetamol is a useful baseline medication in almost all patients, has a slow onset of action and is not readily available for injection, apart from the pro-drug formulation of pro-pacetamol available in many countries. Whereas the rectal administration route is readily available at the end of anaesthesia, the oral route has a more rapid and reliable absorption in the case of paracetamol, and a dose of 1-1.5 g may be given (40-50 mg/kg in children) in a swallow of water about 1 h before start of surgery. Corticosteroids for antiemesis and analgesia have a slow onset of effect and may be given pre-operatively in order to be efficient by the end of anaesthesia.

Per-operative issues:

The principle of co-induction, i.e. to use a low-dose benzodiazepine or analgesic in order to reduce the dose of induction drug and thus fasten recovery do not make much sense with propofol, except for the use of remifentanil. A low dose infusion of remifentanil (i.e. 0.05-0.1 mg/kg/min) before giving propofol may also alleviate some of the aching from propofol. However, as propofol is a more pleasant anxiolytic drug in most patients, an alternative strategy is to start a low dose of propofol (i.e. 1-2 mg/kg/h or serum target of 0.5-1.0 mg/ml) when the patient arrive in the theatre and then increase the target or give a bolus dose when induction of unconsciousness is due. The use of low-dose analgesics before surgery in order to attenuate the wind-up of pain in the dorsal horn of the spinal cord, has not been proven to be an important concept in clinical use, although supported by some experimental data. However, a mixture of opioid analgesics and propofol is useful for attenuating the physiological stress response due to laryngeal mask insertion, surgery and endotracheal intubation. The pharmacokinetics of the opioid chosen and the dose level, are important as to what dose level of propofol should be given. A low dose level of propofol (target of 1-1.5, or 3-5 mg/kg/min) may be used together with remifentanil 0.2-0.5 mg/kg/min, whereas with alfentanil or fentanyl a higher propofol dose may be more appropriate (i.e. target of 2.5-3.5 or 6-10 mg/kg/h) in order not to use too much of an opioid with prolonged recovery profile. Nitrous oxide may be useful, because it reduces the need of propofol with 20-40% and may thus improve both the respiration during the procedure and the speed of recovery afterwards.

Whereas remifentanil is the opioid of choice for outpatient anaesthesia, a simpler setup may be achieved with fentanyl, sufentanil or alfentanil. It is also a clinical impression that it is hard to titrate remifentanil to a reliable spontaneous respiration in all patients, without having a risk of some patients reacting to surgical stimuli. Fentanyl should never be used in high doses in outpatients, but total doses of up to 0.15-0.2 mg may be appropriate if given by the start in procedures where strong postoperative pain is anticipated. Otherwise, alfentanil, 0.5 mg when needed or infusion of 0.5-1 mg/kg/min, gives a better recovery profile and less nausea compared with fentanyl.

Bispectral index (BIS)is primarly a measure of hypnotic effect and may guide the propofol dose more closely, whereas opioids may be adjusted according to signs of stress such as increases in bloodpressure and heart rate. In a spontaneously breathing patient by the end of a procedure, BIS may be allowed to be in the 60-70 range in order to ensue a rapid recovery, whereas during extensive surgery, and especially if the patient is curarized, the level should be in the 40-50 range.

Whereas intubation is rarely indicated in outpatient surgery, cases of prolonged laparoscopy and a major portion of the ENT surgery usually calls for an endotracheal tube. Pharmacokinetic modelling of concommitant peak effects of drugs may be used to avoid the use of muscle relaxants in these patients. A good recepe in children is to start with alfentanil 25 mg/kg, wait for 30 sec, then give propofol 5 mg/kg, ventilate with mask for 1 min, then spray the trachea with concentrated lidocaine (40 mg/ml) , 0.1 ml/kg, ventilate for another 2 min and then intubate at the peak effect of lidocaine and propofol, but before the effect of alfentanil has declined. In adults all these doses should be halved, or reduced even further if combined with a 1xED 95 dose of a muscle relaxant, for instance mivacurium or rapacuronium. A combination of high dose remifentanil and propofol may also be a good alternative for intubation without muscle relaxants.

Post-operative issues:

The pharmacokinetic characteristics of new anaesthetics, such as propofol, remifentanil, desflurane and sevoflurane; means that patients wake up rapidly with no analgesic protection left from the general anaesthetics. Thus, it is important to have established analgesic effect by the end of anaesthesia by other means. The non-opioid and multimodality principles should be applied, as opioids in the post-operative phase may provoke nausea, somnolescense and eventually respiratory depression. Whereas paracetamol and possibly corticosteroids are best given pre-operatively, it is usually recommended to wait with NSAIDs until surgical haemostasis is established, although documentation of this practice is not abundant, apart from some ENT studies. Local anaesthesia in the wound (and joints when applicable) is a very useful adjuvant, given before the patient wake up. In cases of pain in spite of optimal non-opiod prophylaxis, care should be taken to give small, titrated doses of opioid with appropriate onset and duration. Fentanyl is a good option in most cases, if a patient has concommitant pain and shivering pethidine may be the drug of choice. PCA with alfentanil may also be an option. Whereas per-operative propofol and short-acting, low dosed opioids are good measures in order to reduce post-operative nausea and vomiting, some case call for specific anti-emetic prophylaxis, which is most efficient when given by the end of anaesthesia. Many drugs have proven efficient for this purpose: metoclopramid, efedrine, droperidol, ondansetron and corticosteroids.